The Denver Autoimmunity Center of Excellence (ACE) aims to bring together basic and clinical investigators for the study of autoimmune diseases. Projects goals focus on defining susceptibility genes, elucidating immunopathogenesis, developing new therapies, accomplishing clinical trials with novel immunotherapeutic agents, and developing tools to better track new therapies in autoimmune disease. The Denver ACE combines the efforts of investigators with faculty appointments at the University of Colorado Health Sciences Center with affiliations with the Barbara Davis Center for Childhood Diabetes, the National Jewish Medical and Research Center, the University of Nebraska Medical Center, hospitals in Denver, the Rocky Mountain Multiple Sclerosis Center, and the Denver Arthritis Clinic. Faculty has been recruited from multiple departments and programs, and the subspecialties of endocrinology, rheumatology, clinical immunology, nephrology, genetics, dermatology, pulmonary, and gastroenterology. There are unique resources for clinical investigation and strong basic science faculty, and a track record for combining basic and clinical investigation. Another major strength of the current proposal is the breadth of work in Denver studying T cell recognition and biology, genetics, and the biology of inflammatory and cytokine mediators. One unique clinical resource relates to ongoing programs to identify individuals who are at high risk to develop type 1 diabetes. In the current application, three proposed basic projects are 1) to define the non-MHC genetic contributions to a distinct subset of human multiple autoimmune disease syndrome, which appears to be inherited as an autosomal dominant trait with high penetrance; (2) to define the role of complement receptors and complement activation in the immunopathogenesis of type 1 diabetes in the NOD mouse model; and (3) to determine the role of type 1 interferons in the pathogenesis of lupus in an animal model, and whether inhibition of the action of these cytokines can prevent and suppress disease expression. In the current proposal, we also describe the multiple groups pursuing clinical investigation of autoimmune disease relevant to the Centers of Excellence. In addition to clinical trials in lupus and lupus nephritis, two new clinical trials are proposed in this application. Both are Phase II, randomized, double blind, and placebo-controlled in patients early in the disease process. Clinical Project 1 investigates the use of a B9-23 altered peptide ligand to prevent the development of clinical disease in patients with pre-diabetes. Clinical project 2 involves the use of a B cell specific monoclonal antibody to CD20 in the treatment of patients with early rheumatoid arthritis (RA). This latter project involves a newly established collaboration with a separate institution and group of clinicians skilled in the clinical investigation of RA.